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Basic principles of the combination of irradiation and surgery
0360-3016/79/l
Int. .I. Radiation Oncology Eiol. Phys.,, Vol. 5, pp. 2091-20% o Pergamon Press Ltd., 1979. Printed m the U.S.A.
12091-06$02.00/O
??Special Feature
BASIC PRINCIPLES
OF THE COMBINATION SURGERY GILBERT
Professor and Head, Department M.D. Anderson Combination,
Irradiation,
H.
FLETCHER,
M.D.
Surgery.
INTRODUCTION of irradiation and surgery
RADIOBIOLOGICAL
AND
of Radiotherapy, The University of Texas System Cancer Center, Hospital and Tumor Institute, Houston TX 77030
PRESENT
is based on radiobiological as well as clinical considerations. In this communication, these principles are reviewed with specific examples given for various disease areas. The combination
OF IRRADIATION
CONCEPT
OF RADIOCURABILITY
Histology
The radiosensitivity of tumors of various histologic types reflects, to some degree, the radiosensitivity of the tissue of origin, and there are some variations from tissue to tissue. Present clinical data show that all squamous cell carcinomas, adenocarcinemas of the breast and uterus, mucoepidermoid, malignant mixed, adenoid cystic carcinoma of the salivary glands, and possibly soft tissue sarcomas are equally radiosensitive, other factors being equal.
PARAMETERS
The parameters of radiobiology that’apply to clinical radiotherapy are: (1) Cell killing. For the same increment of dose, the same proportion of viable cells are rendered nonviable, which means that with increasing number of malignant clonogens, more radiation is needed for control of a tumor. (2) Hypoxic compartment. Since it takes 2.5 times more irradiation to render hypoxic cells nonviable, a small fraction of hypoxic cells is the determining factor in the dose necessary to control a tumor. (3) With doses up to 200 rad per fraction, single lethal events predominate; whereas at high doses per fraction, multiple sublethal events predominate.fi Single lethal events require less molecular oxygen to produce the same biological damage. (4) Aging of cells during the cell cycle removes cells from the radioresistant S phase and, therefore, as many fractions as possible should be used. (5) With long overall treatment times, there is shrinkage of the tumor with at least partial reoxygenation of the hypoxic compartment. (6) Tumors respond to irradiation and possibly to surgical procedure by an accelerated growth. The “sandwich” technique of irradiation should not be used unless there is a short interval between the pre-operative and post-operative irradiation.
Volume
of cancer
dose control
relationship
The volume of cancer is the determining parameter because the larger the volume, the greater the number of malignant clonogens and the importance of a hypoxic compartment. A small fraction of hypoxic cells increases significantly the dose necessary for a high probability of control. Subclinical
disease
Subclinical disease includes microscopic disease as well as aggregates of cancer cells .that cannot be palpated in accessible areas. Microscopic disease contains relatively few malignant cells that, in undisturbed well-oxygenated tissues like the lymphatics of the neck, are normally oxygenated. Aggregates of cancer cells (1 mm in diameter, approximately lo6 cells) are not microscopic, but in an irradiation scheme of 5 weeks, would become microscopic after a few treatments. Therefore, if there is initially a hypoxic compartment, it will disappear early during the treatment. Several studies have shown that 5,000 rad in 5 weeks eradicates close to 100% of subclini-
Accepted for publication 29 August 1979. Acknowledgement-This investigation was supported in part by Grants CA06294 and CA05654 awarded by the
National Cancer Institute, tion and Welfare. 209 1
Department
of Health,
Educa-
2092
Radiation Oncology 0 Biology 0 Physics
cal deposits in the lymphatics of the neck in the squamous cell carcinoma of the upper respiratory and digestive tracts and adenocarcinoma of the breast. 7 Gross cancer
From clinical data, correlation has been made between probability of control and doses for various volumes of cancer in the control of both primary lesions and metastatic nodes in the adenocarcinomas of the breast and squamous cell carcinomas of the upper respiratory and digestive tracts.lO
POSSIBLE MODALITIES OF COMBINATION Surgery and irradiation can be combined in several ways: (1) Surgery may be used for salvage of irradiation failures. This has been shown effective in many series.2 Irradiation, however, is rarely successful in salvaging surgical failures.g There are two reasons for this: (a) Gross cancer has recurred, and, therefore, the advantage of the greater effectiveness of irradiation on microscopic disease has been lost, and (b) as a rule, surgical failures are rarely localized because there has been implantation of the cancer throughout the entire surgical area. (3) Surgery and irradiation may be used to treat different areas. (4) Surgery and irradiation may be used to cover essentially the same area. The irradiation can be used either pre- or post-operatively. RATIONALE FOR COMBINING IRRADIATION AND SURGERY IN THE SAME AREA Surgical failures occur because not all microscopic disease is removed in all patients, despite the most radical procedures. Failures of irradiation are experienced with gross masses, with the frequency increasing as the volume of cancer increases. Therefore, the two modalities of treatment are complementary: irradiation to eradicate the microscopic disease around the gross masses, and the surgical procedure to remove the gross masses. Partial removal of a tumor achieves little because it does not bring residual disease to the microscopic level and therefore does not eliminate the hypoxic compartment. The word “debulking”. should be used cautiously, since it does not necessarily imply removal of all the gross cancer. PRE- OR POST-OPERATIVE IRRADIATION The combination can be either pre- or postoperative irradiation. Clinical data from M.D. Anderson Hospital show that the local-regional control rates are identical with 5,000 to 6,000 rad given either pre- or post-operatively. The main criticism leveled against the use of post-operative irradiation
November-December
1979, Vol. 5, No. 11 and No. 12
is that it does not diminish the potential for the surgical manipulations to produce distant metastases. That radical surgical procedures can produce distant metastasis was suggested in 1943 from a review of the course of 109 patients having had a radical mastectomy for advanced breast cancer.” Only three patients were alive at 5 years, and they died of distant metastases between 5 and 6 years after surgery. The incidence of recurrences within the operated area was 47.7%. It might be interpreted that radical mastectomy is conducive to producing distant metastases. That distant metastases may be decreased with pre-operative irradiation also has been suggested in one review of head and neck sites.16 When analyzed by anatomical sites, the difference is essentially in the patients with tumors of the paranasal sinuses and oropharynx. In these two anatomical sites, surgical procedures either scrape through or cut close to cancer. In the choice of pre-operative or post-operative irradiation, the important parameters to consider are: (1) The dose of irradiation and the volume irradiated. Healing difficulties increase with higher doses given to larger volumes. (2) The extent of the surgical procedure. After 5,000 rad, a radical neck dissection alone can be performed without healing problems, while a composite operation could be fraught with some morbidity. A very extensive procedure such as laryngopartial pharyngectomy and radical neck dissection is fraught with severe, at times, fatal complications.’ Even with small doses of irradiation, complications can develop when there are fragile suture lines. In a series of patients with resection of pharyngeal wall tumors after 2,500-3,000 rad given in 2*/z to 3 weeks, the local control rates were poor, and the incidence of severe complications was high.15 SHORT TREATMENT SCHEMES An attractive form of combining the two modalities of treatment is to use a few large fractions followed immediately by the surgical procedure; however, several prospective trials in the head and neck area have shown no or only a small advantage . 12,13,19
The ineffectiveness of relatively high doses given in a few fractions could be attributed to: (1) the small component of single-hit lethal events, and, therefore, less effectiveness on the hypoxic cells, (2) lack of reoxygenation of the initially hypoxic cells, and (3) no redistribution of the cells out of the radioresistant phase of the cycle. The isoeffect formulas give false equivalents,
Combination of irradiation and surgery 0 G.H. FLETCHER
2093
_____Plane of excision -
Radiotherapy field widely around gross tumor
Fig. l., Dotted lines indicate a surgical excision that removes gross tumor with close margins. Within the larger rectangle, microscopic disease will be eradicated by irradiation (reproduced with permission from Fletchep).
since they do not take into consideration all radiobiological parameters involved in the relationship of total dose, overall treatment time and fraction size.
EXTENT
OF THE SURGICAL
PROCEDURE
The surgical procedure optimally should be limited to the removal of the gross masses for the following reasons (Fig. 1): (1) With diminished surgical manipulations, there is less opportunity of releasing tumor cells into the blood stream. (2) There is less scar tissue and therefore less possibility of hypoxia for the tumor cells left behind. (3) Post-operative irradiation should be given 3 to 4 weeks following surgery. With very radical surgery
often times using pedicles for reconstruction, it may take months before irradiation can be started. During that time, there is repopulation of the tumor cells, and a gross recurrence is not uncommonly seen when the patient is ready for post-operative irradiation. (4) With conservative surgery, there is a better quality of life preserved. GUIDELINES
FOR THE COMBINED
TREATMENT
Clearly, the choice is to give 5,000 rad preoperatively, provided wound and suture healing and skin grafting allow it. If irradiation is given pre-operatively, it must cover all potentially infested areas. Wide-field irradiation will decrease the likelihood of microscopic disease at the time of the surgical procedure and
Fig. 2. A lo-year-old girl was admitted in June 1971 with a history of left parotidectomy performed in April 1971 for a fixed preauricular mass that had grown rapidly. At operation, the main trunk of the facial nerve was sectioned to remove the tumor mass, and the nerve was then resutured. Histology: poorly differentiated adenocarcinoma. The patient received 5,000 rad at 3 cm depth in 5l/z weeks with combined 18 MeV electrons and photons through a 7 x 8 cm field covering the parotid bed area. The patient showed no evidence of disease in August 1978. She has minimal facial nerve weakness, and the cosmetic result is excellent (reproduced with permission from Tapleyzl).
thereby lower the risk of spreading cancer in the surgical area. If irradiation is given post-operatively, it must cover the entire operated area that is at risk of having been infested by the surgical procedure. In both situations, one should irradiate electively the clinically uninvolved regional lymphatics. By and large, 5,000 rad given in 5 weeks is the maximum dose that can be given pre-operatively, although an extra 1,000 rad may be given through a reduced field to an area of probable, heavy infestation where there will be no suture line. Postoperatively, no less than 5,000 rad should be given to the entire surgical area. A boost of 1,000 rad is given to areas of suspected residual tumor or areas of extensive scarring, because tumor cells locked in
2094
Radiation Oncology 0 Biology 0 Physics
November-December 1979, Vol. 5, No. 11 and No. 12
Fig. 3. A 40-year-old woman presented with pain in the right arm on motion. A 2 x 4 cm subcutaneous mass just anterior to the head of the humerus was excised November 17, 1972, which revealed a high grade fibrosarcoma. (A) A total of 6,600 rad tumor dose was given in 7 weeks using the shrinking field technique. (B) The patient is living free of disease at 6 years
with excellent arm function. A and C reproduced with permission from Lindberg14 and B from Tapley.*O scar tissue may be less radiosensitive. For abdominal or pelvic tumors, the dose is reduced to 4,500 rad.
APPLICATION OF THE COMBINED TREATMENT TO SEVERAL DISEASE AREAS Head and neck With pre- or post-operative irradiation, sugical procedures may be more conservative. For instance, in lesions of the floor of the mouth attached to the periosteum, a coronal resection can be done instead of an Andy-Gump procedure. In tumors of the pyriform sinus, only gross cancer is removed, because as the pharyngectomy is enlarged, there are not only healing problems, but later a severe stricture can develop. In tumors of the parotid, if the facial nerve is not grossly involved, only dissection of the tumor is done; if there is a branch of the facial nerve involved, only that branch is resected (Fig. 2). In the combined treatment of neck nodes, only the hockey stick incision should be used, and
never the classical trifurcate incision. Also, there are degrees of modification to the radical neck dissection that can be used, depending on the clinical situation. The sternocleidomastoid muscle, the jugular vein and the eleventh nerve may be spared. Breast When one uses the combined treatment in breast cancer, there are two procedures which need not be done since they are damaging. (1) Excessive thinning of the flaps. There are no cancer cells in the fat, only in the skin. Thinned and taut flaps heal slowly and can necrose, delaying any needed irradiation of the chest wall. Wound healing is never delayed after a simple mastectomy. Furthermore, because of the diminished vascularization, tumor cells can be rendered hypoxic. (2) The axilla should be modestly dissected when irradiation of the whole axilla has been done preoperatively or is planned post-operatively, because a radical dissection of the axilla is conducive to arm edema, which can be enhanced by irradiation.
Combination of irradiation and surgery 0
Wedge excision and irradiation selected early lesions. Large
have a place in
bowel
The abdominoperitoneal resection simply removes gross cancer, since there is no attempt to dissect the perirectal fat. Since an extensive length of bowel is not removed with the lower anterior resection, there is a risk of recurrence at the anastomotic site. From the irradiation side, one must be careful not to irradiate too large a volume. Attempting to follow the lymph nodes to the root of the mesentery increases significantly the volume irradiated, and there can be complications of the small bowel. Furthermore, if disease is present in the high mesenteric nodes, it is likely that there will be distant metastases. The dose should be limited to 4,500 rad. Gynecology
There is a place for adjunctive surgery in large barrel-shaped lesions of the uterine cervix. It should be a conservative extrafascial hysterectomy done carefully with sharp knife dissection and without removal of part of the parametria. Large lesions can be controlled to a very high percentage with a minimum of complications17 ( communication with W. Wilson, 1978). One should never attempt to do a radical hysterectomy after large doses of irradiation.’ For endometrial cancer, a conservative hysterectomy is performed, either with pre- or post-operative irradiation. For a stage II endometrial cancer, if one chooses to perform a radical hysterectomy, then it
G.H.
2095
FLETCHER
should not be preceded by irradiation. If it is followed by irradiation, the dose has to be at the most 4,000 rad to the whole pelvis. If gross masses only are removed in patients with ovarian cancers, 2,250 rad strip irradiation of the whole abdomen with additional 2,250 rad to the pelvis is very effective.5 For vulvar tumors, 4,000 rad followed by resection of the vulva and a diminished groin node dissection is possibly the best management. Soft tissue sarcomas
The surgical procedures have varied, including simple excision, wide excision, compartmental resection, amputation, and disarticulation. Since softtissue sarcomas often resemble cyst-like tumors, shelling out has resulted in a recurrence rate of approximately 90% because there is not a true capsule but a pseudocapsule around the mass.“*4’1x Even with radical excision, the recurrence rate is 3%.3 Failures, even. after wide excision, are due to the tendency of soft-tissue sarcomas to spread for considerable distances along fascial and muscle planes. For more than 10 years, the treatment of softtissue sarcomas at M.D. Anderson Hospital has been, whenever possible, excision of gross disease followed by post-operative irradiation. From the data now available, this conservative removal followed by irradiation is highly successful and preserves limb function (Fig. 3).i4
REFERENCES C.: Traitement des 1. Cachin, Y., Vandenbrouck, epitheliomas du sinus piriforme et de la margelle laryngee: Etude critique de diverses associations radiochirurgicales. Problemes Actuels D’oto-RhinoLaryngologie: 137-152, 1974. 2. Cadman, N.L., Soule, E.H., Kelly,
P.J.: Synovial sarcoma: An analysis of 134 tumors. Cancer 18: 613-627, 1965. 3. Cantin, J., McNeer, G.P., Chu, F.C., Booher, R.J.: The problem of local recurrences after treatment of soft tissue sarcoma. Ann. Surg. 168: 47-53, 1968. 4. Castro, E.B., Hajdu, S.I., Fortner, J.G.: Surgical therapy of fibrosarcoma of extremities. Arch. Surg. 107: 284-286, 5. Dembo,
1973.
A.J., Bush, R.S., Beale, F.A., Bear, H.A., Pringle, J.F., Sturgeon, J.: Ovarian carcinoma: Improved survival following abdominopelvic irradiation in patients with a completed pelvic operation. Am. J. Obstet. Gynecol. In press. 6. Dutreix, J., Wambersie, A., Bounik, C.: Cellular recovery in human skin reactions. Applications to dose, fraction number, overall time relationship in radiotherapy. Eur. J. Cancer 9: 159-167, 1973. 7. Fletcher, G.H.: Clinical dose response curve of subclinical aggregates of epithelial cells and its practical
application Biological
in the management
of human
cancers.
and Clinical Basis of Radiosensitivity.
In M. 1974,
Friedman, Ed. Springfield, Charles C Thomas. pp. 485-501. 8. Fletcher, G.H.: Combination of irradiation and surgery. In International Advances in Surgical Oncology . G.P. Murphy, Ed., New York, Alan R. Liss, Inc. 1979, 2: 55-98. 9. Fletcher, G.H., Evers, W.Th.: Radiotherapeutic management of surgical recurrences and postoperative residuals in tumors of the head and neck. Radiology 95: 185-188, 10. Fletcher,
1970.
G.H., Shukovsky, L.J.: The interplay of radiocurability and tolerance in the irradiation of human cancers. J. Radiol. Electrol. 56: 383-400, 1975. 11. Haagensen, C.D., Stout, A.P.: Carcinoma of the breast. II. Criteria of operability. Ann. Surg. 118: 859-870, 1943. 12. Ketcham, A.S., Hove, R.C., Chretien, P.B., et al. : Irradiation twenty-four hours preoperatively. Am. J. Surg. 118: 691-697, 13.
1969.
C., et al.: Preoperative irradiation for head and neck cancer. A prospective study. Cancer 33: 318-323, 1974. 14. Lindberg, R.H.: Soft tissue sarcomas. In Textbook of
Lawrence, W., Terz, J.J., Rogers,
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Radiation Oncology 0 Biology 0 Physics
Radiotherapy, 3rd ed., G.H. Fletcher, Philadelphia, Lea & Febiger. 1979, in press. 15. Marks, J.E., Freeman, R.B., Lee, F., Ogura, J.H.: Pharyngeal wall cancer: An analysis of treatment results, complications and patterns of failure. Znt. .Z. Radiat. Oncol. Biol. Phys. 4: 587-593, 1978. 16. Merino, O.R., Lindberg, R.D., Fletcher, G.H.: An analysis of distant metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 46: 145-151, 1977. 17. O’Quinn, A.G., Fletcher, G.H., Wharton, J.T.: Guidelines for conservative hysterectomy after irradia-
November-December 1979, Vol. 5, No. 11 and No. 12
tion. Gynecol. Oncol., 1979, in press. 18. Shieber, W., Graham, P.: An experience with sarcoma of the soft tissue in adults. Surgery 52: 295-298, 1962. 19. Strong, E.W.: Preoperative radiation and radical neck dissection. Surg. Clin. No. Am. 49: 271-276, 1969. 20. Tapley, N. duV.: Clinical Applications of the Electron Beam. New York, John Wiley and Sons, Publishers, 1976, p. 239. 21. Tapley, N. duV.: The place of irradiation in the treatment of malignant tumors of the salivary gland. Ear, Nose, Throat 56: 110-114, 1977.
Int. .I. Radiation Oncology Eiol. Phys.,, Vol. 5, pp. 2091-20% o Pergamon Press Ltd., 1979. Printed m the U.S.A.
12091-06$02.00/O
??Special Feature
BASIC PRINCIPLES
OF THE COMBINATION SURGERY GILBERT
Professor and Head, Department M.D. Anderson Combination,
Irradiation,
H.
FLETCHER,
M.D.
Surgery.
INTRODUCTION of irradiation and surgery
RADIOBIOLOGICAL
AND
of Radiotherapy, The University of Texas System Cancer Center, Hospital and Tumor Institute, Houston TX 77030
PRESENT
is based on radiobiological as well as clinical considerations. In this communication, these principles are reviewed with specific examples given for various disease areas. The combination
OF IRRADIATION
CONCEPT
OF RADIOCURABILITY
Histology
The radiosensitivity of tumors of various histologic types reflects, to some degree, the radiosensitivity of the tissue of origin, and there are some variations from tissue to tissue. Present clinical data show that all squamous cell carcinomas, adenocarcinemas of the breast and uterus, mucoepidermoid, malignant mixed, adenoid cystic carcinoma of the salivary glands, and possibly soft tissue sarcomas are equally radiosensitive, other factors being equal.
PARAMETERS
The parameters of radiobiology that’apply to clinical radiotherapy are: (1) Cell killing. For the same increment of dose, the same proportion of viable cells are rendered nonviable, which means that with increasing number of malignant clonogens, more radiation is needed for control of a tumor. (2) Hypoxic compartment. Since it takes 2.5 times more irradiation to render hypoxic cells nonviable, a small fraction of hypoxic cells is the determining factor in the dose necessary to control a tumor. (3) With doses up to 200 rad per fraction, single lethal events predominate; whereas at high doses per fraction, multiple sublethal events predominate.fi Single lethal events require less molecular oxygen to produce the same biological damage. (4) Aging of cells during the cell cycle removes cells from the radioresistant S phase and, therefore, as many fractions as possible should be used. (5) With long overall treatment times, there is shrinkage of the tumor with at least partial reoxygenation of the hypoxic compartment. (6) Tumors respond to irradiation and possibly to surgical procedure by an accelerated growth. The “sandwich” technique of irradiation should not be used unless there is a short interval between the pre-operative and post-operative irradiation.
Volume
of cancer
dose control
relationship
The volume of cancer is the determining parameter because the larger the volume, the greater the number of malignant clonogens and the importance of a hypoxic compartment. A small fraction of hypoxic cells increases significantly the dose necessary for a high probability of control. Subclinical
disease
Subclinical disease includes microscopic disease as well as aggregates of cancer cells .that cannot be palpated in accessible areas. Microscopic disease contains relatively few malignant cells that, in undisturbed well-oxygenated tissues like the lymphatics of the neck, are normally oxygenated. Aggregates of cancer cells (1 mm in diameter, approximately lo6 cells) are not microscopic, but in an irradiation scheme of 5 weeks, would become microscopic after a few treatments. Therefore, if there is initially a hypoxic compartment, it will disappear early during the treatment. Several studies have shown that 5,000 rad in 5 weeks eradicates close to 100% of subclini-
Accepted for publication 29 August 1979. Acknowledgement-This investigation was supported in part by Grants CA06294 and CA05654 awarded by the
National Cancer Institute, tion and Welfare. 209 1
Department
of Health,
Educa-
2092
Radiation Oncology 0 Biology 0 Physics
cal deposits in the lymphatics of the neck in the squamous cell carcinoma of the upper respiratory and digestive tracts and adenocarcinoma of the breast. 7 Gross cancer
From clinical data, correlation has been made between probability of control and doses for various volumes of cancer in the control of both primary lesions and metastatic nodes in the adenocarcinomas of the breast and squamous cell carcinomas of the upper respiratory and digestive tracts.lO
POSSIBLE MODALITIES OF COMBINATION Surgery and irradiation can be combined in several ways: (1) Surgery may be used for salvage of irradiation failures. This has been shown effective in many series.2 Irradiation, however, is rarely successful in salvaging surgical failures.g There are two reasons for this: (a) Gross cancer has recurred, and, therefore, the advantage of the greater effectiveness of irradiation on microscopic disease has been lost, and (b) as a rule, surgical failures are rarely localized because there has been implantation of the cancer throughout the entire surgical area. (3) Surgery and irradiation may be used to treat different areas. (4) Surgery and irradiation may be used to cover essentially the same area. The irradiation can be used either pre- or post-operatively. RATIONALE FOR COMBINING IRRADIATION AND SURGERY IN THE SAME AREA Surgical failures occur because not all microscopic disease is removed in all patients, despite the most radical procedures. Failures of irradiation are experienced with gross masses, with the frequency increasing as the volume of cancer increases. Therefore, the two modalities of treatment are complementary: irradiation to eradicate the microscopic disease around the gross masses, and the surgical procedure to remove the gross masses. Partial removal of a tumor achieves little because it does not bring residual disease to the microscopic level and therefore does not eliminate the hypoxic compartment. The word “debulking”. should be used cautiously, since it does not necessarily imply removal of all the gross cancer. PRE- OR POST-OPERATIVE IRRADIATION The combination can be either pre- or postoperative irradiation. Clinical data from M.D. Anderson Hospital show that the local-regional control rates are identical with 5,000 to 6,000 rad given either pre- or post-operatively. The main criticism leveled against the use of post-operative irradiation
November-December
1979, Vol. 5, No. 11 and No. 12
is that it does not diminish the potential for the surgical manipulations to produce distant metastases. That radical surgical procedures can produce distant metastasis was suggested in 1943 from a review of the course of 109 patients having had a radical mastectomy for advanced breast cancer.” Only three patients were alive at 5 years, and they died of distant metastases between 5 and 6 years after surgery. The incidence of recurrences within the operated area was 47.7%. It might be interpreted that radical mastectomy is conducive to producing distant metastases. That distant metastases may be decreased with pre-operative irradiation also has been suggested in one review of head and neck sites.16 When analyzed by anatomical sites, the difference is essentially in the patients with tumors of the paranasal sinuses and oropharynx. In these two anatomical sites, surgical procedures either scrape through or cut close to cancer. In the choice of pre-operative or post-operative irradiation, the important parameters to consider are: (1) The dose of irradiation and the volume irradiated. Healing difficulties increase with higher doses given to larger volumes. (2) The extent of the surgical procedure. After 5,000 rad, a radical neck dissection alone can be performed without healing problems, while a composite operation could be fraught with some morbidity. A very extensive procedure such as laryngopartial pharyngectomy and radical neck dissection is fraught with severe, at times, fatal complications.’ Even with small doses of irradiation, complications can develop when there are fragile suture lines. In a series of patients with resection of pharyngeal wall tumors after 2,500-3,000 rad given in 2*/z to 3 weeks, the local control rates were poor, and the incidence of severe complications was high.15 SHORT TREATMENT SCHEMES An attractive form of combining the two modalities of treatment is to use a few large fractions followed immediately by the surgical procedure; however, several prospective trials in the head and neck area have shown no or only a small advantage . 12,13,19
The ineffectiveness of relatively high doses given in a few fractions could be attributed to: (1) the small component of single-hit lethal events, and, therefore, less effectiveness on the hypoxic cells, (2) lack of reoxygenation of the initially hypoxic cells, and (3) no redistribution of the cells out of the radioresistant phase of the cycle. The isoeffect formulas give false equivalents,
Combination of irradiation and surgery 0 G.H. FLETCHER
2093
_____Plane of excision -
Radiotherapy field widely around gross tumor
Fig. l., Dotted lines indicate a surgical excision that removes gross tumor with close margins. Within the larger rectangle, microscopic disease will be eradicated by irradiation (reproduced with permission from Fletchep).
since they do not take into consideration all radiobiological parameters involved in the relationship of total dose, overall treatment time and fraction size.
EXTENT
OF THE SURGICAL
PROCEDURE
The surgical procedure optimally should be limited to the removal of the gross masses for the following reasons (Fig. 1): (1) With diminished surgical manipulations, there is less opportunity of releasing tumor cells into the blood stream. (2) There is less scar tissue and therefore less possibility of hypoxia for the tumor cells left behind. (3) Post-operative irradiation should be given 3 to 4 weeks following surgery. With very radical surgery
often times using pedicles for reconstruction, it may take months before irradiation can be started. During that time, there is repopulation of the tumor cells, and a gross recurrence is not uncommonly seen when the patient is ready for post-operative irradiation. (4) With conservative surgery, there is a better quality of life preserved. GUIDELINES
FOR THE COMBINED
TREATMENT
Clearly, the choice is to give 5,000 rad preoperatively, provided wound and suture healing and skin grafting allow it. If irradiation is given pre-operatively, it must cover all potentially infested areas. Wide-field irradiation will decrease the likelihood of microscopic disease at the time of the surgical procedure and
Fig. 2. A lo-year-old girl was admitted in June 1971 with a history of left parotidectomy performed in April 1971 for a fixed preauricular mass that had grown rapidly. At operation, the main trunk of the facial nerve was sectioned to remove the tumor mass, and the nerve was then resutured. Histology: poorly differentiated adenocarcinoma. The patient received 5,000 rad at 3 cm depth in 5l/z weeks with combined 18 MeV electrons and photons through a 7 x 8 cm field covering the parotid bed area. The patient showed no evidence of disease in August 1978. She has minimal facial nerve weakness, and the cosmetic result is excellent (reproduced with permission from Tapleyzl).
thereby lower the risk of spreading cancer in the surgical area. If irradiation is given post-operatively, it must cover the entire operated area that is at risk of having been infested by the surgical procedure. In both situations, one should irradiate electively the clinically uninvolved regional lymphatics. By and large, 5,000 rad given in 5 weeks is the maximum dose that can be given pre-operatively, although an extra 1,000 rad may be given through a reduced field to an area of probable, heavy infestation where there will be no suture line. Postoperatively, no less than 5,000 rad should be given to the entire surgical area. A boost of 1,000 rad is given to areas of suspected residual tumor or areas of extensive scarring, because tumor cells locked in
2094
Radiation Oncology 0 Biology 0 Physics
November-December 1979, Vol. 5, No. 11 and No. 12
Fig. 3. A 40-year-old woman presented with pain in the right arm on motion. A 2 x 4 cm subcutaneous mass just anterior to the head of the humerus was excised November 17, 1972, which revealed a high grade fibrosarcoma. (A) A total of 6,600 rad tumor dose was given in 7 weeks using the shrinking field technique. (B) The patient is living free of disease at 6 years
with excellent arm function. A and C reproduced with permission from Lindberg14 and B from Tapley.*O scar tissue may be less radiosensitive. For abdominal or pelvic tumors, the dose is reduced to 4,500 rad.
APPLICATION OF THE COMBINED TREATMENT TO SEVERAL DISEASE AREAS Head and neck With pre- or post-operative irradiation, sugical procedures may be more conservative. For instance, in lesions of the floor of the mouth attached to the periosteum, a coronal resection can be done instead of an Andy-Gump procedure. In tumors of the pyriform sinus, only gross cancer is removed, because as the pharyngectomy is enlarged, there are not only healing problems, but later a severe stricture can develop. In tumors of the parotid, if the facial nerve is not grossly involved, only dissection of the tumor is done; if there is a branch of the facial nerve involved, only that branch is resected (Fig. 2). In the combined treatment of neck nodes, only the hockey stick incision should be used, and
never the classical trifurcate incision. Also, there are degrees of modification to the radical neck dissection that can be used, depending on the clinical situation. The sternocleidomastoid muscle, the jugular vein and the eleventh nerve may be spared. Breast When one uses the combined treatment in breast cancer, there are two procedures which need not be done since they are damaging. (1) Excessive thinning of the flaps. There are no cancer cells in the fat, only in the skin. Thinned and taut flaps heal slowly and can necrose, delaying any needed irradiation of the chest wall. Wound healing is never delayed after a simple mastectomy. Furthermore, because of the diminished vascularization, tumor cells can be rendered hypoxic. (2) The axilla should be modestly dissected when irradiation of the whole axilla has been done preoperatively or is planned post-operatively, because a radical dissection of the axilla is conducive to arm edema, which can be enhanced by irradiation.
Combination of irradiation and surgery 0
Wedge excision and irradiation selected early lesions. Large
have a place in
bowel
The abdominoperitoneal resection simply removes gross cancer, since there is no attempt to dissect the perirectal fat. Since an extensive length of bowel is not removed with the lower anterior resection, there is a risk of recurrence at the anastomotic site. From the irradiation side, one must be careful not to irradiate too large a volume. Attempting to follow the lymph nodes to the root of the mesentery increases significantly the volume irradiated, and there can be complications of the small bowel. Furthermore, if disease is present in the high mesenteric nodes, it is likely that there will be distant metastases. The dose should be limited to 4,500 rad. Gynecology
There is a place for adjunctive surgery in large barrel-shaped lesions of the uterine cervix. It should be a conservative extrafascial hysterectomy done carefully with sharp knife dissection and without removal of part of the parametria. Large lesions can be controlled to a very high percentage with a minimum of complications17 ( communication with W. Wilson, 1978). One should never attempt to do a radical hysterectomy after large doses of irradiation.’ For endometrial cancer, a conservative hysterectomy is performed, either with pre- or post-operative irradiation. For a stage II endometrial cancer, if one chooses to perform a radical hysterectomy, then it
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should not be preceded by irradiation. If it is followed by irradiation, the dose has to be at the most 4,000 rad to the whole pelvis. If gross masses only are removed in patients with ovarian cancers, 2,250 rad strip irradiation of the whole abdomen with additional 2,250 rad to the pelvis is very effective.5 For vulvar tumors, 4,000 rad followed by resection of the vulva and a diminished groin node dissection is possibly the best management. Soft tissue sarcomas
The surgical procedures have varied, including simple excision, wide excision, compartmental resection, amputation, and disarticulation. Since softtissue sarcomas often resemble cyst-like tumors, shelling out has resulted in a recurrence rate of approximately 90% because there is not a true capsule but a pseudocapsule around the mass.“*4’1x Even with radical excision, the recurrence rate is 3%.3 Failures, even. after wide excision, are due to the tendency of soft-tissue sarcomas to spread for considerable distances along fascial and muscle planes. For more than 10 years, the treatment of softtissue sarcomas at M.D. Anderson Hospital has been, whenever possible, excision of gross disease followed by post-operative irradiation. From the data now available, this conservative removal followed by irradiation is highly successful and preserves limb function (Fig. 3).i4
REFERENCES C.: Traitement des 1. Cachin, Y., Vandenbrouck, epitheliomas du sinus piriforme et de la margelle laryngee: Etude critique de diverses associations radiochirurgicales. Problemes Actuels D’oto-RhinoLaryngologie: 137-152, 1974. 2. Cadman, N.L., Soule, E.H., Kelly,
P.J.: Synovial sarcoma: An analysis of 134 tumors. Cancer 18: 613-627, 1965. 3. Cantin, J., McNeer, G.P., Chu, F.C., Booher, R.J.: The problem of local recurrences after treatment of soft tissue sarcoma. Ann. Surg. 168: 47-53, 1968. 4. Castro, E.B., Hajdu, S.I., Fortner, J.G.: Surgical therapy of fibrosarcoma of extremities. Arch. Surg. 107: 284-286, 5. Dembo,
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A.J., Bush, R.S., Beale, F.A., Bear, H.A., Pringle, J.F., Sturgeon, J.: Ovarian carcinoma: Improved survival following abdominopelvic irradiation in patients with a completed pelvic operation. Am. J. Obstet. Gynecol. In press. 6. Dutreix, J., Wambersie, A., Bounik, C.: Cellular recovery in human skin reactions. Applications to dose, fraction number, overall time relationship in radiotherapy. Eur. J. Cancer 9: 159-167, 1973. 7. Fletcher, G.H.: Clinical dose response curve of subclinical aggregates of epithelial cells and its practical
application Biological
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and Clinical Basis of Radiosensitivity.
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Friedman, Ed. Springfield, Charles C Thomas. pp. 485-501. 8. Fletcher, G.H.: Combination of irradiation and surgery. In International Advances in Surgical Oncology . G.P. Murphy, Ed., New York, Alan R. Liss, Inc. 1979, 2: 55-98. 9. Fletcher, G.H., Evers, W.Th.: Radiotherapeutic management of surgical recurrences and postoperative residuals in tumors of the head and neck. Radiology 95: 185-188, 10. Fletcher,
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G.H., Shukovsky, L.J.: The interplay of radiocurability and tolerance in the irradiation of human cancers. J. Radiol. Electrol. 56: 383-400, 1975. 11. Haagensen, C.D., Stout, A.P.: Carcinoma of the breast. II. Criteria of operability. Ann. Surg. 118: 859-870, 1943. 12. Ketcham, A.S., Hove, R.C., Chretien, P.B., et al. : Irradiation twenty-four hours preoperatively. Am. J. Surg. 118: 691-697, 13.
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C., et al.: Preoperative irradiation for head and neck cancer. A prospective study. Cancer 33: 318-323, 1974. 14. Lindberg, R.H.: Soft tissue sarcomas. In Textbook of
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Radiotherapy, 3rd ed., G.H. Fletcher, Philadelphia, Lea & Febiger. 1979, in press. 15. Marks, J.E., Freeman, R.B., Lee, F., Ogura, J.H.: Pharyngeal wall cancer: An analysis of treatment results, complications and patterns of failure. Znt. .Z. Radiat. Oncol. Biol. Phys. 4: 587-593, 1978. 16. Merino, O.R., Lindberg, R.D., Fletcher, G.H.: An analysis of distant metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 46: 145-151, 1977. 17. O’Quinn, A.G., Fletcher, G.H., Wharton, J.T.: Guidelines for conservative hysterectomy after irradia-
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tion. Gynecol. Oncol., 1979, in press. 18. Shieber, W., Graham, P.: An experience with sarcoma of the soft tissue in adults. Surgery 52: 295-298, 1962. 19. Strong, E.W.: Preoperative radiation and radical neck dissection. Surg. Clin. No. Am. 49: 271-276, 1969. 20. Tapley, N. duV.: Clinical Applications of the Electron Beam. New York, John Wiley and Sons, Publishers, 1976, p. 239. 21. Tapley, N. duV.: The place of irradiation in the treatment of malignant tumors of the salivary gland. Ear, Nose, Throat 56: 110-114, 1977.